Glycosaminoglycans to Treat and Prevent Radiation-Induced Oral Mucositis

项目摘要/摘要 口腔粘膜炎是一种令人痛苦的炎症性疾病，常发生在癌症治疗过程中。 影响了50万美国人。伴随而来的疼痛非常严重，患者经常需要麻醉剂。 止痛药。临床表现为口腔和胃肠道溃疡，分别为 机会性感染加剧了这种情况。许多患者还患有口干，导致口腔功能障碍。 吞咽是因为唾液腺功能下降。因此，这些患者经常需要喂食。 中断他们癌症治疗的管子。患者的经济负担高得令人震惊，代价高昂 每名患者额外支付17,000至40,000美元。预防口腔粘膜炎将极大地增强癌症 治疗以及患者的健康。GlycoMira的领先候选人GM-1111是一种新的反 每天一次给药时调节过度活跃的先天免疫系统的炎症性药物 皮下注射。SBIR第一阶段和第二阶段的研究结果表明，它在降低 放射性口腔粘膜炎模型中的严重程度和疾病发生：GM-1111降低 舌头组织溃烂和发炎。组织学上，GM-1111处理组的口腔组织 上皮损伤明显减轻，白细胞轻度渗入，粘膜层增厚 与赋形剂处理的对照组相比，防止粘液腺变化。 生化和基因表达分析显示，Toll样蛋白的表达增加 受体、NLRP3炎症体及其下游促炎细胞因子，所有这些都是 经GM-1111处理后降低。总体而言，数据表明GM-1111有很大的潜力降低 人类的口腔粘膜炎。GlycoMira还制造了符合cGMP的GM-1111，并产生了其 制造规格。为了进一步开发一种商业上可行的口腔粘膜炎治疗方法，我们 建议将用于研究新药(IND)申请的研究提交给FDA进行临床试验。 目的是(1)描述GM-1111在非临床研究和(2)生产中的安全性 临床试验准备好的无菌药物产品(无菌灌装/包装和标签/包装)并测试其稳定性。这个 建议的研究结果将通过IND应用将药物开发引导到临床阶段 并推动该药物对患有这种毁灭性疾病的患者的商业化。

Project Summary/Abstract Oral mucositis is a devastatingly painful inflammatory disease that frequently develops during cancer therapy and affects half a million Americans. The accompanying pain is so severe that patients often require narcotic pain medicines. The clinical manifestations are ulcers in the mouth and gastrointestinal tract, which are exacerbated by opportunistic infections. Many patients also suffer from dry mouth causing difficulty in swallowing because of the decreased salivary gland function. As a result, these patients often need feeding tubes which interrupts their cancer treatment. The financial burden to the patient is staggeringly high, costing an additional $17,000 to $40,000 for each patient. Preventing oral mucositis will greatly enhance the cancer therapy as well as the wellness of the patients. GlycoMira's lead candidate, GM-1111, is a new class of anti- inflammatory drugs that modulate an overactive innate immune system when administered via once daily subcutaneous injection. The SBIR Phase I and II study results demonstrate its powerful efficacy in reducing the severity and the occurrence of the disease in radiation-induced oral mucositis models: GM-1111 reduced tissue ulceration and inflammation in the tongue. Histologically, oral tissues from the GM-1111 treated group showed markedly reduced damages in the epithelium with mild infiltration of leukocytes, thicker mucosal layers and prevention of mucous glandular alterations compared to the tissues from vehicle treated controls. Biochemical and gene expression analyses of the diseased tissues revealed increased expression of Toll-like receptors, NLRP3 inflammasome as well as their downstream pro-inflammatory cytokines all of which were reduced with GM-1111 treatment. Overall, the data suggest that GM-1111 has substantial potential to reduce oral mucositis in humans. GlycoMira also manufactured cGMP compliant GM-1111 and generated its manufacturing specifications. To further develop a commercially viable therapeutic for oral mucositis, we propose studies that will be used for the Investigative New Drug (IND) application to the FDA for clinical trials. The objectives are to (1) delineate the safety profiles of GM-1111 in nonclinical studies and (2) manufacture clinical trial ready sterile drug product (aseptic fill/finish and labeling/packaging) and test its stability. The results of the proposed research will lead the drug development to the clinical stage through IND application and propel the commercialization of the drug to the patients suffering from this devastating disease.